Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-trifluoroacetyl Meldrum's acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one and their synthetic usefulness as (trifluoroacetyl)ketene precursors

Article abstract of DOI:10.1016/j.tet.2017.01.065

A simple and reliable method for the preparation of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one on a multigram scale was developed. These (trifluoroacetyl)ketene precursors were used in the hetero-Diels-Alder reaction with dialkylcyanamides and 1-ethoxyprop-1-yne, as well as in some reactions with nucleophiles.

Full text of DOI:10.1016/j.tet.2017.01.065

Accepted Manuscript
Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-
trifluoroacetyl Meldrum's acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-
one and their synthetic usefulness as (trifluoroacetyl)ketene precursors
Dmitri V. Sevenard, Andrey V. Didenko, Denis Lorenz, Michael Vorobiev, Johannes
Stelten, Thomas Dülcks, Vyacheslav Ya Sosnovskikh
PII:
S0040-4020(17)30100-X
10.1016/j.tet.2017.01.065
TET 28435
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 October 2016
Revised Date: 16 January 2017
Accepted Date: 26 January 2017
Please cite this article as: Sevenard DV, Didenko AV, Lorenz D, Vorobiev M, Stelten J, Dülcks T,
Sosnovskikh VY, Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione
(2-trifluoroacetyl Meldrum's acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one and
their synthetic usefulness as (trifluoroacetyl)ketene precursors, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.01.065.
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1
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Graphical abstract
_______________________________________________________________________________
Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-trifluoroacetyl Meldrum’s
acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one and their synthetic usefulness as
(trifluoroacetyl)ketene precursors
Dmitri V. Sevenard,* Andrey V. Didenko, Denis Lorenz, Michael Vorobiev, Johannes Stelten, Thomas Dülcks and
Vyacheslav Ya. Sosnovskikh
________________________________________________________________________

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ACCEPTED MANUSCRIPT
Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione
(2-trifluoroacetyl Meldrum’s acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-
1,3-dioxin-4-one and their synthetic usefulness as (trifluoroacetyl)ketene
precursors
Dmitri V. Sevenard a,*, Andrey V. Didenko a, Denis Lorenz a, Michael Vorobiev a, Johannes
Stelten b, Thomas Dülcks b, Vyacheslav Ya. Sosnovskikh c
a Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstr. 1, 28359 Bremen, Germany
b Institute of Organic and Analytical Chemsitry, University of Bremen, Leobener Str. 1, 28359 Bremen,
Germany
c Institute of Natural Sciences, Ural Federal University, pr. Lenina 51, 620000 Ekaterinburg, Russian
Federation
* Corresponding author. E-mail address: sevenard@hfc-chemicals.com
A B S T R A C T
A simple and reliable method for the preparation of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-
4,6-dione and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one on a multigram scale was
developed. These (trifluoroacetyl)ketene precursors were used in the hetero-Diels-Alder reaction
with dialkylcyanamides and 1-ethoxyprop-1-yne, as well as in some reactions with nucleophiles.
Keywords: Fluorinated compounds, (Trifluoroacetyl)ketene, Meldrum’s acid, Hetero-Diels-Alder
reaction, Trifluoroacetoacetylation, Preparative method
1. Introduction
For other project, ongoing in our laboratory, we required a sample of trifluoroacetoacetylated N-
(2-hydroxyethyl)phthalimide 1. A literature survey showed that this compound can be prepared by
alcoholysis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-trifluoroacetylated
Meldrum’s acid 2) described by Yamamoto and coworkers in 1997,1 which reacted with tert-butyl
alcohol in chloroform at room temperature, yielding 80% of tert-butyl trifluoroacetoacetate. It was
also shown in the same work that maintaining the acid 2 in chloroform solution in the presence of
acetone for 2 days gave a moderate yield of 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one

2
ACCEPTED MANUSCRIPT
3, which properties have not been studied. It was proposed by the authors that the transformation 2
→ 3 proceeds via the formation of (trifluoroacetyl)ketene 4, followed by [4+2] cycloaddition at the
carbonyl group of acetone1 (Scheme 1).
The dioxin 3 was first obtained in 1995 by trifluoroacetylation of in situ generated ketene with
trifluoroacetic anhydride in the presence of acetone, but the yield was merely 8%.2 Among its
closest analogs, syntheses of 5-substituted 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-ones 5
have been reported, using the respective ketenes, trifluoroacetic anhydride, and acetone;2,3 6-
(trifluoromethyl)-4-oxo-1,3-dioxin-2-spirocyclohexane 6 was obtained from 4,4,4-trifluoro-3-
oxobutanoic acid, cyclohexanone, and acetic anhydride in the presence of sulfuric acid,4 and 2,2-
dimethyl-5-(trifluoromethyl)-4H-1,3-dioxin-4-one 7 was also obtained from 2,2-dimethyl-5-iodo-
4H-1,3-dioxin-4-one, trifluoromethyliodide, and copper powder in HMPA as a solvent5 (Scheme 1).
O
O
N
O
CF3
O
O
1
H
O
O
O
O
CDCl3, Me2CO,
rt, 2 days
O
O
CF3
Me
Me
Me
Me
-CO2
F3C
O
O
2
3
-CO2
O
C
O
+
Me
Me
F3C
O
4
O
O
O
F3C
R
O
O
O
Me
Me
Me
Me
O
F3C
O
F3C
O
5
6
7
Scheme 1. Target 1,3-ketoester 1 and known fluorinated-4H-1,3-dioxin-4-ones.
2. Results and discusion
Despite the obvious synthetic importance of compounds 2 and 3, which can be considered as a
source of the highly reactive (trifluoroacetyl)ketene 4, the methods suitable for their preparation

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have been described only in one brief report,1 without information about yields, spectral and
analytical data. In the work1 the authors propose a method for the synthesis of 2-trifluoroacetylated
Meldrum’s acid 2 by treatment of Meldrum’s acid with N-(trifluoroacetyl)imidazole in the presence
of imidazole in chloroform at room temperature, followed by washing the reaction mixture with
10% aqueous HCl. Even though an analogous approach was also used for the trifluoroacetylation of
1,3-cyclohexanediones,6 we failed to reproduce the synthesis of acid 2 under those conditions
despite numerous attempts. The presence of imidazolium salt 8 of the desired tricarbonyl compound
19
in reaction mixture was detected in all cases by 1H and F NMR spectroscopy, but it decomposed
to 4,4,4-trifluoro-3-oxobutanoic acid 9, trifluoroacetic acid, and the starting Meldrum’s acid when
3–10% aqueous HCl or 5% aqueous citric acid was added for the removal of imidazole, while only
trace amounts of the target compound 2 were observed. Only the use of HCl in diethyl ether
(saturated solution was diluted with equal amount of diethyl ether) allowed to obtain the
trifluoroacetylated acid 2 in mixture with dioxin 3 and trifluoroacetoacetic acid 9 (2:3:9 = 20:10:1).
Pure compound 2 could be isolated in 24% yield by washing solid imidazolium chloride with
chloroform, followed by removal of solvent under vacuum without heating (the conversion of acid
2 to dioxin 3 was accelerated by heating). It should be noted that the use of saturated HCl solution
in diethyl ether immediately converted the salt 8 to dioxin 3. The attempt to synthesize compound 2
by reaction of Meldrum’s acid with trifluoroacetic anhydride in the presence of Et3N and DMAP
was not successful (Scheme 2). Tautomeric features of compounds 2 and 9 are discussed in
Supporting Information.

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O
N
O
+
N COCF3
Me
Me
O
O
N
rt, CHCl3
NH
O
O
O
NH
NH
N
H
O
CF3
Me
Me
N
O
8
Cl
N
H
HCl,
Et2O
NH
H
O
O
O
HO
CF3
O
CF3
O
+
+
Me
Me
Me
Me
O
H
O
O
O
F3C
O
2
9
3
2:3:9 = 20:10:1
Scheme 2. Synthesis of 2-trifluoroacetylated Meldrum’s acid 2.
As mentioned above, an important reactivity feature of dioxane 2 was its spontaneous
decarboxylation to dioxin 3. Indeed, we found that this transformation occurred not only in CDCl3
solution at room temperature (2:3:9 = 91:7:2 after 2 h, 52:44:4 after 22 h, 6:63:31 after 100 h), but
also in solid state at –30 °C (2:3:9 = 90:6:4 after 10 days and 56:33:11 after 4 months). The
transformation 2 → 3 in CHCl3 solution in the presence of acetone was complete in 16 h and
provided dioxin 3 in quantitative yield according to NMR. The dioxin 3 has been characterized in
the literature2 as colorless oil, unstable at room temperature and decomposing completely in 24 h.
According to our data, the decomposition rate for this compound in closed vessel at ~20 °C to the
acid 9 and 1,1,1-trifluoroacetone was fairly slow (3:9:trifluoroacetone = 85:7:8 after 24 h both in
CDCl3 and in solid state), and it could be stored for a few months at –30 °C. When a drop of water
was added to an NMR sample of compound 3 in CDCl3, we observed its complete conversion to the
acid 9 within 7 days, accompanied by partial decarboxylation to 1,1,1-trifluoroacetone.
Taking into account the fact that compound 2 represents a masked form of
(trifluoroacetyl)ketene 4,1 it is logical to propose that dioxin 3 can also serve as its precursor. We
compared the reactivity of precursors 2 and 3 in hetero-Diels-Alder reactions with

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dialkylcyanamides and 1-ethoxyprop-1-yne, and established that both compounds 2 and 3 gave the
same products 10–12, but the reactions with dioxin 3 always occurred faster and gave higher yields
of products. For example, refluxing the compound 3 with dimethyl- and diethylcyanamides in
benzene for 1.5 h gave 2-dialkylamino-6-trifluoromethyl-1,3-oxazin-4-ones 10 and 11 in 60% and
48% yields, respectively, while the yield of product 10 from dioxane 2 was merely 19% after
refluxing for 20 h. Based on these data, we can propose that the reaction of dioxane 2 with
dienophiles involves the formation of compound 3 as intermediate, according to the route 2 → 3 →
4 (Scheme 3).
The reaction of compounds 2 and 3 with 1-ethoxyprop-1-yne was observed to produce a mixture
of regioisomeric 4-pyrones 12a and 12b in 6:1 ratio (again, these products were obtained in better
yields and purity from the dioxin 3, than from dioxane 2). The regioisomers 12a,b could be
separated chromatographically, and pure samples were prepared for analysis by using preparative
TLC. For the purpose of structure determination, the obtained mixture was heated with ammonia in
ethanol for 16 h, leading to the pyridines 13a and 13b as products of 4-pyrone 12а transformation7
in 46% and 8% yields, respectively, after isolation by column chromatography. The regiochemistry
1
of pyridine 13а was established by an H–13C HMBC 2D NMR experiment, with the most
informative cross peaks of H-5/C-3, H-5/C-7, H-7/C-3, H-7/C-2, H-7/C-4 and H-8/C-2, allowing to
exclude the isomeric structure 13с from consideration. It should be noted that pyridine 13с was not
detected even in trace amounts, because the minor 4-pyrone 12b did not react with ammonia and
was recovered in unchanged form. This fact indicates that the initial attack by ammonia molecule
on pyrone 12а occurred at position 2, which was deactivated by the presence of methyl group in
pyrone 12b. In order to elucidate the mechanism for the formation of pyridine 13b, we treated
compound 13а with excess of 25% aqueous ammonia and found that the reaction did not proceed
upon refluxing in 1,4-dioxane and even with heating in autoclave (1,4-dioxane, 140°C, 16 h), and
pyridine 13а was completely recovered. Obviously, the substitution of ethoxy group with amino
group occurred prior to the formation of pyridine ring.

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O
O
R2N CN
N
2 or 3
[4]
C6H6, , 1.5 h
F3C
NR2
10 (R = Me, 60%)
11 (R = Et, 48%)
C6H6,
, 14 h
Me
OEt
O
4
O
Me
OEt
5
3
+
6
2
F3C
O
OEt
F3C
O
Me
12a
12b
12a:12b = 6:1
EtOH,
NH3
90 oC, 16 h
OH
N
OH
7
Me
4
Me
5
3
+
8
6
2
F3C
NH2
F3C
N
OCH2Me
13b (8%)
13a (46%)
OH
OEt
Me
F3C
N
13c
Scheme 3. Hetero-Diels-Alder reactions of 2 and 3.
In the 1Н NMR spectrum of pyridine 13а taken in СDCl3 the signal of H-5 proton at δ 6.75 ppm
was found, instead of the expected δ 7.10–7.28 ppm range for a regioisomer of type 13с.8 Besides
that, 13С NMR spectrum of this compound showed three downfield signals belonging to carbon
nuclei bonded to heteroatoms, while 4 such signals should be expected for its isomer 13с.8 The
most downfield 13C NMR signals of pyridines 13a and 13b were singlets at δ 163.6 and 161.7 ppm,
respectively, in agreement with the structure of 4-pyridinol (the 4-pyridone carbonyl signal is
usually above 170 ppm8а). Thus, the main product of (trifluoroacetyl)ketene 4 reaction with 1-
ethoxyprop-1-yne had the structure of 2-ethoxy-4-pyrone 12а, also in agreement with literature
data9 describing the transformation of related non-fluorinated 4-pyrones to 4-hydroxypyridines.
Mass spectra (EI) of compounds 2 and 3 displayed the expected ion with m/z 138, due to
(trifluoroacetyl)ketene radical cation generated by fragmentation through the retro-Diels-Alder
mechanism (its molecular formula C4HF3O2 was confirmed by HRMS). However, this signal was
totally absent in the mass spectrum of compound 12b, while another fragment with m/z 139 was
observed instead (the same peak, although much weaker, was also present in the mass spectrum of
dioxin 3). The presence of this ion can be explained by ring opening via α-cleavage at the carbonyl

7
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group and hydrogen atom transfer through a 6-membered transition state after the appropriate
conformational change (Scheme 4). Remarkably, the mass spectra of pyridines 13a,b also did not
show the ion with m/z 137 from decomposition by retro-Diels-Alder mechanism. Instead, another
strong peak with m/z 138 was observed, with the molecular formula (C4H3F3NO) confirmed by
HRMS. The formation of this ion can be explained analogously. Thus, the fragmentation pathways
proposed in Scheme 4 appear to be preferred when compared to the expected retro-Diels-Alder
reaction, and significant amounts of 4-pyridone tautomer of 13 is present in the gas phase.
O
O
O
CH2
C
H
O
OEt
Me
+
[12b]
C
m/z 222
F3C
O
F3C
O
F3C
O
OEt
OEt
m/z 139
O
O
H
CH2
O
O
[3]
+
Me
Me
Me
Me
F3C
O
m/z 196
F3C
O
F3C
O
O
m/z 139
O
O
O
O
NH
C
H
Me
Me
NH
+
NH
C
F3C
N
H
NH2
F3C
N
NH2
F3C
N
H
F3C
Me
H
Me
m/z 138
13b
m/z 192
Scheme 4. Fragmentation pathways in mass spectra (EI) of compounds 3, 12b and 13b.
With a reliable method for the synthesis of dioxane 2 in hand, we studied its reaction with N-(2-
hydroxyethyl)phthalimide. As expected, the target compound 1 was obtained in 35% yield as a
stable covalent hydrate 14, when reacted in dichloromethane at room temperature. The use of dioxin
3 in this reaction allowed to increase the yield of product 14 to 43%. In contrast to the thoroughly
studied acetoacetylation reaction using 2,6,6-trimethyl-1,3-dioxin-4-one,10 this is the first known
example when alcohols were trifluoroacetoacetylated by the action of 2,2-dimethyl-6-
(trifluoromethyl)-4H-1,3-dioxin-4-one 3. The reaction of hydrazine hydrate with compound 2 in
dimethoxyethane at room temperature began with the formation of salt 15, which was transformed
in acetic acid to the previously known11 pyrazole 16 in 21% yield. This transformation can also be
interpreted as trifluoroacetoacetylation of hydrazine followed by intramolecular cyclization at the
trifluoroacetyl group (Scheme 5).

8
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O
OH
O
N
O
O
O
2 or 3
N
CH2Cl2, rt,
24 h (for 2),
6 days (for 3)
CF3
OH
HO
O
14
O
O NH3NH2
F3C
N2H4•H2O
DME, rt, 1 h
AcOH
O
CF3
N
2
Me
Me
OH
rt, 60 h
N
H
O
O
15
16
HS
OMe
F3C
S
2 or 3
CH2Cl2, rt, 7 days
H2O
OH
O
OMe
17
F3C
S
F3C
S
HO OH
O
O
O
OMe
OMe
Scheme 5. Synthesis of compounds 14, 16 and 17.
We further studied the thiophenol trifluoroacetoacetylation, aiming the preparation of a little-
known trifluoromethylated β-ketothioesters. Treatment of compounds 2 or 3 with 4-
methoxythiophenol in dichloromethane provided the thioester 17 in 20% and 49% yields,
respectively (Scheme 5). In the 1Н and 19F NMR spectra of this product taken in CDCl3 three sets of
signals in 86:13:1 ratio were found, corresponding to hydrate (CH2 singlet at 3.09 ppm, broadened
singlet of two ОН groups at 4.8 ppm, CF3 at –87.2 ppm), enol form (ОН at 12.2 ppm, =СН at 6.02
ppm, CF3 at –74.8 ppm), and keto form (CH2 singlet at 4.01 ppm, CF3 at –79.2 ppm), respectively.
It should be noted that (trifluoromethyl)ketones are well known to exist as gem-diols12 due to the
electron-withdrawing effect of the CF3 group.
3. Conclusion
We have developed reliable procedures for the preparation of trifluoroacetylated Meldrum’s acid
and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one on a multigram scale, enabling their
complete characterization. These valuable CF3-containing building blocks were demonstrated to
serve a source of the highly reactive (trifluoroacetyl)ketene. As trifluoroacetoacetylating agent and

9
ACCEPTED MANUSCRIPT
diene component in hetero-Diels-Alder reaction, 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-
one is considerably superior to its precursor 2. The reported compounds are of particular synthetic
interest, demonstrated in reactions with a range of nucleophiles and dienophiles.
4. Experimental section
4.1. General
NMR spectra were recorded on Bruker WB-360 (1Н – 360.2 MHz), Bruker DRX-400 (13С –
100.6 MHz), Bruker DPX-200 (1Н – 200.1 MHz, 13С – 50.3 MHz and 19F – 188.3 MHz) and Bruker
19
AC-200 (1Н – 200.1 MHz and F – 188.1 MHz) spectrometers at room temperature. Chemicals
13
shifts are reported relative Me4Si (1H and C: δ = 0.00 ppm) and CFCl3 (19F: δ = 0.00 ppm). As
internal standards the residual solvent proton signals (2.50 ppm for DMSO-d6, 7.25 ppm for CDCl3,
1.94 ppm for CD3CN and 7.15 ppm for C6D6 solutions), CDCl3 and DMSO-d6 signals (13C: 77.0
and 39.4 ppm, respectively) and C6F6 signal (19F: –162.2 ppm) were used. Assignment of signals in
13C NMR spectra based on carbon-fluorine couplings, the results of DEPT 135 (for compounds 3,
1
13, 14 and 17) and 2D H–13C HMBC experiments (13a) measured on Bruker DPX-200
spectrometer. The mass spectra were recorded on a Finnigan MAT 95 double-focusing mass-
spectrometer (EI, 70 eV, direct inlet). High-resolution measurements (HRMS) were performed on
the same instrument using the peak matching method at a resolution of 10000 (10% valley).
Reagents were purchased and were used as received without further purification. The reactions were
carried out in oven-dried glassware under static N2 atmosphere. The solvents were dried using
standard procedures: CH2Cl2 and CHCl3 from P2O5, benzene, THF, DME and diethyl ether from
sodium/benzophenone ketyl). Silica gel 0.060–0.200 mm, 60 Å (Acros Organics) was used for
column chromatography.
4.2. 1-Ethoxy-1-propyne
This compound was prepared using procedure published earlier.13 1H NMR (CDCl3) δ: 1.32 (t,
3H, Me, J = 7.1 Hz), 1.72 (s, Me), 4.00 (q, 2H, CH2, J = 7.1 Hz). The product contained ca. 3 mol%
of 1-ethoxyallene [1H NMR (CDCl3) δ: 1.25 (t, 3H, Me, J = 6.7 Hz), 3.61 (q, 2H, CH2, J = 6.7 Hz),
5.41 (d, 2H, H-1, J = 5.3 Hz), 6.70 (dd, 1H, H-1, J = 5.3, 5.1 Hz)] as admixture.
4.3. N-(Trifluoroacetyl)imidazole

10
ACCEPTED MANUSCRIPT
This compound was prepared by modified procedure published earlier.14 To a pre-cooled (5 °C)
and well-stirred absolute THF (100 mL) trifluoroacetic anhydride (80 g, 380 mmol) was added
carefully. The solution formed was added to a pre-cooled (5 °C) and well-stirred solution of
imidazole (51.6 g, 759 mmol) in absolute THF (240 mL) carefully. The mixture was stirred for 1 h
at ambient temperature, and left at 0 °C overnight. The solid precipitate was filtered off and washed
with diethyl ether (25 mL). The filtrate was concentrated in vacuo without heating and the residue
was distilled to provide the desired product. Yield 49 g (79%), hydrolytically sensitive colorless
1
liquid, very moisture sensitive, bp 73–75 °C (100 Torr) (lit.14 45–46 °C (14 Torr)). H NMR
19
(CDCl3) δ: 7.21 (dd, 1H, H-4, J = 1.8, 0.8 Hz), 7.55 (m, 1H, H-5), 8.24 (s, 1H, H-2). F NMR
(CDCl3) δ: –71.3 (s, CF3). The parameters in agreement with published data.15
4.4. 2,2-Dimethyl-5-(trifluoroacetyl)-1,3-dioxan-4,6-dione (2-trifluoroacetyl Meldrum’s acid)
(2)
4.4.1. To a solution of imidazole (7.15 g, 105 mmol) in anhydrous CHCl3 (180 mL) 2,2-dimethyl-
1,3-dioxan-4,6-dione (15.1 g, 105 mmol) was added at room temperature. To the mixture a solution
of N-(trifluoroacetyl)imidazole (18.1 g, 105 mmol) in CHCl3 (180 mL) was added carefully under
stirring within 30 min. The solvent from the yellowish solution formed (contains salt 8 as the only
fluorinated compound as revealed by 19F NMR) was removed in vacuo without heating. The yellow
oily residue [bis-imidazolium 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxan-4,6-dionate 8: yield
1
100%, yellow oil; H NMR (CDCl3) δ: 1.71 (s, 6H, 2 Me), 7.23 (s, 4H, imidazolium), 8.11 (s, 2H,
19
imidazolium), 14.08 (s, 3H, 3 NH); F NMR (CDCl3) δ: –73.0 (s, CF3)] was dissolved in CHCl3
(50 mL), cooled down to –30 °C and half-saturated HCl solution in diethyl ether (150 mL, prepared
by dilution of saturated solution with diethyl ether 1:1) was added under vigorous stirring. The
mixture was stirred for 15 min at ambient temperature, and the precipitate of imidazolium chloride
was filtered off under N2 atmosphere. The volatiles from the filtrate were removed in vacuo without
heating to provide the mixture of dioxane 2, dioxine 3, and ketoacid 9 (20:10:1 as estimated by 1H
and 19F NMR spectra) as a yellow waxy solid (10 g). The precipitate of imidazolium chloride above
was washed with CHCl3 (2 x 100 mL), the solvent was removed in vacuo without heating to
provide pure 2 in yield 6.0 g (24%), white solid, mp 87–88 °C (decomp.). 1H NMR (CDCl3) δ: 1.79
(s, 6H, 2 Me), 16.1 (br. s, 1H, OH). 19F NMR (CDCl3) δ: –70.9 (s, CF3). 13C NMR (CDCl3) δ: 26.8,
91.9, 107.5, 117.1 (q, J = 280.6 Hz, CF3), 155.6, 172.3, 175.2 (q, J = 39.9 Hz, COCF3). MS (27 °C),
m/z (Irel (%)): 240 [M]+ (3), 225 (18), 138 (3), 69 (32), 58 (31), 43 (100). HRMS: m/z [M]+ found:
240.0242. Calc. for C8H7F3O5: 240.0240; 0.59 ppm. HRMS: m/z 138 found: 137.9926. Calc. for
C4HF3O2: 137.9923; 1.77 ppm.

11
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4.4.2. 4,4,4-Trifluoro-3-oxobutanoic acid (9). The precipitate of imidazolium chloride above was
washed with anhydrous diethyl ether (2 x 50 mL), the solvent was removed in vacuo without
heating to leave crude ketoacid 9. Yield 0.5 g (3%), yellowish solid, mp 54–55 °C. Enol (C+D),
1
19
keto (E) and hydrate (F) forms in 76:12:12 ratio were detected using H and F NMR for this
sample of acid 9 dissolved in CDCl3. The analytical sample was obtained by sublimation of the
crude product in vacuo at ambient temperature. Colorless prisms, mp 79–81 °C, (C+D):E:F =
63:10:27 ratio were detected at room temperature in the freshly prepared CDCl3 solution. MS (56
°C), m/z (Irel (%)): 156 [M]+ (35), 139 (20), 119 (10), 112 (53), 97 (3), 87 (85), 69 (100).
4.4.2.1. Enol (C+D): 1H NMR (CDCl3) δ: 5.69 (s, 1H, =СH), 8.0 (br. s, 1H, CO2H), 11.3 (br. s, 1H,
OH). 19F NMR (CDCl3) δ: –75.1 (s, CF3). 13C NMR (CDCl3) δ: 91.6 (q, C-2, J = 3.5 Hz), 118.2 (q,
J = 275.0 Hz, CF3), 161.7 (q, J = 36.8 Hz, С-3), 175.7 (C-1).
1
19
4.4.2.2. Keto-form E: H NMR (CDCl3) δ: 3.82 (s, 2H, CH2), 8.0 (br. s, 1H, CO2H). F NMR
(CDCl3) δ: –79.3 (s, CF3).
1
4.4.2.3. Hydrate F: H NMR (CDCl3) δ: 2.91 (s, 2H, CH2), 6.5 (br. s, 2H, 2 OH), 8.0 (br. s, 1H,
CO2H). 19F NMR (CDCl3) δ: –87.4 (s, CF3).
4.5. 2,2-Dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one (3)
4.5.1. Method A. To a solution of 2 (2.4 g, 10 mmol) in anhydrous CHCl3 (40 mL) acetone (10 mL)
was added. The mixture was stirred for 1 h at ambient temperature and then heated (bath
temperature 50 °C) for 16 h (CO2 evolution observed). The volatiles were removed in vacuo to
provide pure compound 3. Yield 1.55 g (79%), yellowish liquid. 1H NMR (CDCl3) δ: 1.77 (s, 6H, 2
Me), 5.90 (s, 1H, H-5). 1H NMR (C6D6) δ: 1.00 (s, 6H, 2 Me), 5.41 (s, 1H, H-5). 19F NMR (CDCl3)
19
13
δ: –74.9 (s, CF3). F NMR (C6D6) δ: –74.4 (s, CF3). C NMR (CDCl3) δ: 24.6 (Me), 96.8 (q, J =
2.9 Hz, C-5), 109.3, 117.9 (q, J = 273.2 Hz, CF3), 154.7 (q, J = 39.8 Hz, C-6), 158.9. MS (26 °C),
m/z (Irel (%)): 196 [M]+ (11), 181 (5), 139 (2), 138 (1), 69 (18), 58 (41), 43 (100). Found (%): C,
42.60; H, 3.55. Calc. for C7H7F3O3 (%): C, 42.87; H, 3.60.
4.5.2. Method B. To a solution of imidazole (17.7 g, 260 mmol) in anhydrous CHCl3 (350 mL) 2,2-
dimethyl-1,3-dioxan-4,6-dione (37.4 g, 260 mmol) was added at room temperature. To this mixture
a solution of N-(trifluoroacetyl)imidazole (45.0 g, 274 mmol) in CHCl3 (260 mL) was added

12
ACCEPTED MANUSCRIPT
carefully under stirring within 30 min; 2/3 of the solvent from the yellowish solution of salt 8 was
removed in vacuo without heating. The residue was cooled down to –30 °C and half-saturated HCl
solution in diethyl ether (300 mL) was added under vigorous stirring. The mixture was stirred for 15
min at ambient temperature, the precipitate of imidazolium chloride was filtered off and washed
with CHCl3 (2 x 100 mL). The volatiles from the filtrate were removed in vacuo to provide the
yellow waxy solid which consists of compounds 2 and 3 in 1:2.9 ratio with traces of acid 9 (1H and
19F NMR data). The solid was dissolved in CHCl3 (300 mL) and acetone (150 mL) was added. The
mixture was stirred for 20 min at ambient temperature and then heated (bath temperature 50 °C) for
20 h (CO2 evolution observed). The volatiles were removed in vacuo to provide crude compound 3
which is pure enough (ca. 90% assay by NMR) to be used without further purification for the most
applications. Yield 34 g (ca. 60%). If necessary, the product can be purified by distillation,
however, the considerable tar formation takes place and the losses of the substance are significant:
2.0 g of the crude product being distilled gave 1.0 g of the pure compound 3 as a colorless liquid, bp
62–65 °C (12 Torr).
4.5.3. Method C. To a solution of imidazole (0.72 g, 10.5 mmol) in anhydrous CHCl3 (18 mL) 2,2-
dimethyl-1,3-dioxan-4,6-dione (1.51 g, 10.5 mmol) was added at room temperature. To the mixture
a solution of N-(trifluoroacetyl)imidazole (1.81 g, 110 mmol) in CHCl3 (18 mL) was added
carefully under stirring within 30 min. The solvent from the yellowish solution of salt 8 was
removed in vacuo without heating. The yellow oily salt 8 was dissolved in CHCl3 (5 mL), cooled
down to –30 °C and saturated HCl solution in diethyl ether (15 mL) was added under vigorous
stirring. The mixture was stirred for 15 min at ambient temperature, and the precipitate of
imidazolium chloride was filtered off under N2 atmosphere. The volatiles from the filtrate were
removed in vacuo to provide compound 2 with admixture of acid 9 (8%). Yield 1.1 g (ca. 49%).
4.6. 2-Dimethylamino-6-(trifluoromethyl)-1,3-oxazin-1H-4-one (10)
4.6.1. Method A. To a solution of compound 3 (400 mg, 2 mmol) in dry benzene (10 mL)
dimethylcyanamide (150 mg, 2.1 mmol) was added and the mixture was heated at reflux for 1.5 h.
The volatiles were removed in vacuo and crude product was recrystallized from heptane/toluene
1
(5:1). Yield 250 mg (60%), yellow crystals, mp 100–101 °C. H NMR (CDCl3) δ: 3.14, 3.19 (both
s, each one 3H, Me2N), 6.36 (s, 1H, H-5). 19F NMR (CDCl3) δ: –73.3 (s, CF3). 13C NMR (CDCl3) δ:
36.1, 37.9, 107.1 (q, C-5, J = 2.8 Hz), 117.7 (q, CF3, J = 272.9 Hz), 149.6 (q, C-6, J = 40.4 Hz),
156.9, 165.7. Found (%): C, 40.20; H, 3.25; N, 13.33. Calc. for C7H7F3N2O2 (%): C, 40.39; H, 3.39;
N, 13.46.

13
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4.6.2. Method B. To a solution of compound 2 (120 mg, 0.50 mmol) in dry benzene (2 mL)
dimethylcyanamide (40 mg, 0.57 mmol) was added and the mixture was heated on reflux for 20 h.
The volatiles were removed in vacuo, and compound 10 was isolated by column chromatography
(EtOAc/hexane, 1:2 to 2:1) of the crude product. Yield 20 mg (19%).
4.7. 2-Diethylamino-6-(trifluoromethyl)-1,3-oxazin-1H-4-one (11)
This compound was synthesized according to method А for compound 10 from dioxin 3 (13.2 g, 67
mmol) and diethylcyanamide (6.9 g, 70 mmol) in dry benzene (150 mL). Compound 11 was
isolated by column chromatography (EtOAc/hexane, 1:1) of the crude product (fraction with Rf =
1
0.4 was collected). Yield 7.6 g (48%), orange crystals, mp 44–46 °C. H NMR (CDCl3) δ: 1.13–
19
1.35 (m, 6H, 2 Me), 3.44, 3.60 (both q, each one 2H, 2 CH2, J = 6.8 Hz), 6.36 (s, 1H, H-5). F
NMR (CDCl3) δ: –73.6 (s, CF3). 13C NMR (CDCl3) δ: 12.4, 13.5, 42.4, 43.7, 107.3 (q, C-5, J = 2.8
Hz), 117.8 (q, CF3, J = 272.8 Hz), 149.6 (q, C-6, J = 40.4 Hz), 156.2, 165.9. Found (%): C, 45.70;
H, 4.61; N, 11.64. Calc. for C9H11F3N2O2 (%): C, 45.77; H, 4.69; N, 11.86.
4.8. Reaction of 3 with 1-ethoxy-1-propyne
To a solution of compound 3 (3.9 g, 20 mmol) in dry benzene (60 mL) 1-ethoxy-1-propyne (2.5
g, 30 mmol) was added. The mixture was heated at reflux (CaCl2-drying tube) for 14 h. The yellow
solution formed (containing 12a and 12b in 6:1 ratio, 19F NMR yield 79%) was evaporated in vacuo
and the residue was distilled. The fraction boiling in the range 60–70 °C (1 Torr) solidified to
yellow waxy solid (1.6 g), which consists of 12a and 12b in 5.6:1 ratio; their analytical samples
were obtained by preparative TLC (EtOAc/hexane, 1:5).
4.9. Reaction of 2 with 1-ethoxy-1-propyne
To a solution of compound 2 (60 mg, 0.25 mmol) in dry benzene (5 mL) 1-ethoxy-1-propyne (85
mg, 1 mmol) was added. The mixture was heated at reflux for 16 h. The 19F NMR monitoring of the
reaction mixture (a yellow solution) revealed the complete conversion of compound 2 with the
complex mixture of several products, where 12a and 12b in 6:1 ratio could be identified (19F NMR
virtual yield ca. 20%).

14
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4.9.1. 2-Ethoxy-3-methyl-6-(trifluoromethyl)-4Н-pyran-4-one (12а). Colorless waxy solid, mp 49–
1
51 °C, Rf = 0.3. H NMR (CDCl3) δ: 1.44 (t, 3H, Me, J = 7.0 Hz), 1.87 (s, 3H, Me), 4.40 (q, 2H,
CH2, J = 7.0 Hz), 6.64 (s, 1H, H-5). 19F NMR (CDCl3) δ: –71.7 (s, CF3).
4.9.2. 3-Ethoxy-2-methyl-6-(trifluoromethyl)-4Н-pyran-4-one (12b). Colorless crystals, mp 114–
1
115 °C, Rf = 0.4. H NMR (CDCl3) δ: 1.44 (t, 3H, Me, J = 7.0 Hz), 1.98 (s, 3H, Me), 4.17 (q, 2H,
CH2, J = 7.0 Hz), 6.62 (s, 1H, H-5). 19F NMR (CDCl3) δ: –71.5 (s, CF3). MS (22 °C), m/z (Irel (%)):
222 [M]+ (100), 207 (2), 194 (62), 117 (4), 166 (100), 153 (14), 139 (15), 125 (40), 97 (30), 83 (14),
69 (34), 43 (4).
4.10. Reaction of 12 with ammonia
To a solution of the mixture 12a and 12b from the previous experiment (0.86 g, 5.6:1 ratio) in
ethanol (50 mL) 25% aq. NH3 (2 mL) was added and the stirred mixture was heated at 90 °C for 16
h. The red solution formed was poured onto water (500 mL) and after extraction with diethyl ether
(4 × 30 mL) the combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried
(Na2SO4) and evaporated. The pyridines 13 have been isolated by column chromatography (CHCl3
as an eluent); pyridine 13b was purified additionally by preparative TLC (EtOAc/hexane, 1:5).
4.10.1. 2-Ethoxy-4-hydroxy-3-methyl-6-(trifluoromethyl)pyridine (13а). Yield 330 mg (46%),
1
colorless crystals, mp 59–60 °C, Rf = 0.55 (EtOAc/hexane, 1:5). H NMR (CDCl3) δ: 1.37 (t, 3H,
H-9, J = 7.0 Hz), 2.09 (s, 3H, H-7), 4.40 (q, 2H, CH2, J = 7.0 Hz), 5.6 (br. s, 1H, OH), 6.75 (s, 1H,
H-5). 1H NMR (DMSO-d6) δ: 1.30 (t, 3H, H-9, J = 6.9 Hz), 1.98 (s, 3H, H-7), 4.29 (q, 2H, CH2, J =
19
19
6.9 Hz), 6.89 (s, 1H, H-5), 11.1 (br. s, 1H, OH). F NMR (CDCl3) δ: –69.3 (s, CF3). F NMR
(DMSO-d6) δ: –67.5 (s, CF3). 13C NMR (CDCl3) δ: 7.7 (C-7), 14.5 (C-9) , 62.6 (C-8), 103.3 (q, C-5,
J = 3.0 Hz), 108.6 (C-3), 121.5 (q, CF3, J = 273.7 Hz), 142.9 (q, C-6, J = 35.4 Hz), 161.8 (C-4),
163.6 (C-2). MS (24 °C), m/z (Irel (%)): 221 [M]+ (52), 206 (100), 193 (90), 192 (51), 176 (7), 164
(21), 138 (75), 69 (7). Found (%): C, 48.95; H, 4.70; N, 6.31. Calc. for C9H10F3NO2 (%): C, 48.87;
H, 4.56; N, 6.33.
4.10.2. 2-Amino-4-hydroxy-3-methyl-6-(trifluoromethyl)pyridine (13b). Yield 50 mg (8%), white
1
powder, mp 135 °C (subl., from toluene/EtOH, 5:1), Rf = 0.13 (EtOAc/hexane, 1:5). H NMR
(CDCl3) δ: 2.04 (s, 3H, Me), 4.6 (br. s, 2H, NH2), 5.9 (br. s, 1H, OH), 6.57 (s, 1H, H-5). 1H NMR
19
(DMSO-d6) δ: 1.89 (s, 3H, Me), 6.0 (br. s, 2H, NH2), 6.51 (s, 1H, H-5), 10.4 (br. s, 1H, OH). F
19
13
NMR (CDCl3) δ: –69.1 (s, CF3). F NMR (DMSO-d6) δ: –67.5 (s, CF3). C NMR (DMSO-d6) δ:

15
ACCEPTED MANUSCRIPT
8.9 (Me), 98.6 (q, C-5, J = 3.0 Hz), 103.5, 122.0 (q, CF3, J = 274.2 Hz), 142.7 (q, C-6, J = 32.5 Hz),
160.1, 161.7. MS (120 °C), m/z (Irel (%)): 192 [M]+ (100), 173 (10), 172 (25), 163 (15), 144 (12),
138 (25), 69 (2). HRMS: m/z [M]+ found: 192.0505. Calc. for C7H7F3N2O: 192.0505; 0.16 ppm.
HRMS: m/z 138 found: 138.0156. Calc. for C4H3F3NO: 138.0161; –3.5 ppm.
4.11. 2-(N-Phthalimido)ethyl 4,4,4-trifluoro-3,3-dihydroxybutanoate (14)
4.11.1. Method A. To a solution of compound 2 (240 mg, 1 mmol) in anhydrous CH2Cl2 (3 mL) N-
(2-hydroxyethyl)phthalimide (200 mg, 1 mmol) was added. The mixture was maintained in the
sealed flask for 24 h at ambient temperature and the volatiles were removed in vacuo. The residue
was subjected to column chromatography (EtOAc/hexane, 1:1) to provide the compound 14 (Rf =
1
0.4). Yield 120 mg (35%), white powder, mp 108 °C (subl.). H NMR (CD3CN) δ: 2.73 (s, 2H,
CH2), 3.92, 4.38 (both t, each one 2H, 2 CH2, J = 5.3 Hz), 5.31 (s, 2H, 2 OH), 7.78–7.88 (m, 4H,
19
1
Ar). F NMR (CD3CN) δ: –87.3 (s, CF3). H NMR (CD3CN+CDCl3) δ: 2.71 (s, 2H, CH2), 3.93,
4.37 (both t, each one 2H, 2 CH2, J = 5.4 Hz), 7.69–7.88 (m, 4H, Ar). 19F NMR (CD3CN+CDCl3) δ:
13
–86.2 (s, CF3). С NMR (CD3CN+CDCl3) δ: 37.1, 38.5, 63.2 (C-4), 92.7 (q, C-3, J = 33.2 Hz),
123.0 (q, CF3, J = 284.5 Hz), 123.7, 134.8 (both s, Ar), 132.4 (Ci), 168.6, 170.6. Found (%): C,
48.57; H, 3.65; N, 4.00. Calc. for C14H12F3NO6 (%): C, 48.42; H, 3.48; N, 4.03.
4.11.2. Method B. To a solution of compound 3 (20 mg, 0.1 mmol) in anhydrous CH2Cl2 (0.5 mL)
N-(2-hydroxyethyl)phthalimide (20 mg, 1 mmol) was added. The mixture was maintained in the
sealed flask for 6 days at ambient temperature (19F NMR monitoring), and the volatiles were
removed in vacuo. The residue was subjected to preparative TLC (EtOAc/hexane, 1:1) to provide
the compound 14. Yield 15 mg (43%).
4.12. 5-Hydroxy-3-(trifluoromethyl)-1H-pyrazole (16)
To a well stirred solution of compound 2 (220 mg, 0.92 mmol) in absolute DME (3 mL) 100%
hydrazine hydrate (50 mg, 1 mmol) was added at ambient temperature and the mixture was stirred
for 1 h. In the solution formed the salt, hydrazinium 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxan-
19
4,6-dionate, is the only fluorinated species present, as revealed by F NMR. The volatiles were
removed in vacuo to provide crude salt 15 as a beige powder [1H NMR (CDCl3+DMSO-d6) δ: 1.37
+
19
(s, 6H, 2 Me), 6.8 (br. s, 5H, NH3NH2); F NMR (CDCl3+DMSO-d6) δ: –72.5 (s, CF3)]. This
powder was dissolved in acetic acid (10 mL) and the solution was maintained for 60 h at ambient
temperature. After evaporation of the solvent the yellow oily residue was subjected to column

16
ACCEPTED MANUSCRIPT
chromatography (CHCl3/MeOH, 10:1) to provide pyrazole 16. Yield 30 mg (21%), colorless solid,
mp 139–141 °C (lit.11с mp 135–137 °C). 1H NMR (CDCl3+acetone-d6) δ: 5.51 (s, 1H, H-4), 9.1 (br.
s, 2H, NH, OH, exchangeable with CD3CO2D). 19F NMR (CDCl3+acetone-d6) δ: –62.8 (s, CF3).
4.13. S-(4-Methoxyphenyl) 4,4,4-trifluoro-3-oxobutanethioate (17)
4.13.1. Method A. To a solution of compound 3 (0.80 g, 4.1 mmol) in anhydrous CH2Cl2 (35 mL) 4-
(methoxy)thiophenol (0.57 g, 4.1 mmol) was added. The solution formed was maintained for 7 days
in the sealed flask at ambient temperature (19F NMR monitoring). The volatiles were removed in
vacuo, the oily residue left was subjected to column chromatography (EtOAc/hexane, 1:5) to
provide ketothioester 17. Yield 600 mg (49%), white solid, mp 65–66 °C, Rf = 0.30.
1
Hydrate:enol:keto forms in 86:13:1 ratio were detected using H and 19F NMR in the freshly
prepared CDCl3 solution at room temperature. MS (32 °C), m/z (Irel (%)): 296 [M]+ (2), 278 (4), 140
(100), 139 (20), 125 (30), 97 (5), 69 (27). HRMS: m/z [M]+ found: 296.0317. Calc. for
C11H11F3O4S: 296.0325; –2.62 ppm.
1
4.13.1.1. Enol: H NMR (CDCl3) δ: 3.84 (s, 3H, MeO), 6.03 (s, 1H, =CH), 6.98, 7.37 (AA'BB'-
19
system (dd), each one 2H, Ar, JAB = JA'B' = 9.0 Hz), 12.2 (br. s, 1H, OH). F NMR (CDCl3) δ: –
74.9 (s, CF3).
4.13.1.2. Keto-form: 1H NMR (CDCl3) δ: 4.01 (s, 2H, CH2). 19F NMR (CDCl3) δ: –79.2 (s, CF3).
4.13.1.3. Hydrate: 1H NMR (CDCl3) δ: 3.09 (s, 2H, CH2), 3.83 (s, 3H, MeO), 4.8 (br. s, 2H, 2 OH),
6.96, 7.34 (AA'BB'-system (dd), each one 2H, Ar, JAB = JA'B' = 8.6 Hz). 19F NMR (CDCl3) δ: –87.2
13
(s, CF3). C NMR (CDCl3) δ: 43.6 (C-2), 55.3 (Me), 93.3 (q, J = 33.4 Hz, С-3), 115.1, 136.0
(CHAr), 121.9 (q, J = 286.0 Hz, CF3), 132.6, 161.2, 199.2.
4.13.2. Method B. To a solution of compound 2 (80 mg, 0.33 mmol) in anhydrous CH2Cl2 (3 mL) 4-
(methoxy)thiophenol (45 mg, 0.33 mmol) was added. The solution formed was maintained for 5
days in the sealed flask at ambient temperature. The volatiles were removed in vacuo, the oily
residue left was subjected to preparative TLC (EtOAc/hexane, 1:5) to provide ketothioester 17.
Yield 20 mg (20%).
Acknowledgement

17
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Mrs. D. Kemken, Institute of Organic Chemistry, University of Bremen, Germany, is thanked
for recording the mass spectra.
References
1. Morita, Y.; Kamakura, R.; Takeda, M.; Yamamoto, Y. Chem. Commun. 1997, 359.
2. Boivin, J.; El Kaim, L.; Zard, S. Z. Tetrahedron 1995, 51, 2585.
3. Cho, J.; Irie, S.; Iwahashi, N.; Itoh, Y.; Saigo, K.; Ishida, Y. Tetrahedron Lett. 2015, 56, 127.
4. (a) Iwaoka, T.; Murohashi, T.; Sato, M.; Kaneko, C. Synthesis 1992, 977; (b) Chiang, Y.;
Kresge, A. J.; Meng, Q.; Morita, Y.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 8345.
5. Iwaoka, T.; Murohashi, T.; Katagiri, N.; Sato, M.; Kaneko, C. J. Chem. Soc., Perkin Trans 1
1992, 1393.
6. (a) Khlebnicova, T. S.; Isakova, V. G.; Baranovsky, A. V.; Borisov, E. V.; Lakhvich, F. A. J.
Fluorine Chem. 2006, 127, 1564; (b) Szczeciński, P.; Gryff-Keller, A.; Molchanov, S. J. Org.
Chem. 2006, 71, 4636; (c) Bondy, S. C.; Cannizzaro, C. E.; Chou, C.-H.; Halcomb, R. L.; Hu,
Y. E.; Link, J. O.; Liu, Q.; Schroeder, S. D.; Tse W. C.; Zhang, J. R. Patent WO2013/6738,
2013.
7. Usachev, B. I. J. Fluorine Chem. 2015, 172, 80.
8. (a) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reißig, H.-U. Chem. Eur. J. 2004, 10, 4283; (b)
Lechel, T.; Dash, J.; Hommes, P.; Lentz, D.; Reissig, H.-U. J. Org. Chem. 2010, 75, 726.
9. Kato, T.; Yamamoto, Y.; Takeda, S. Chem. Pharm. Bull. 1973, 21, 1047.
10. (a) Clemens R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431; (b) Sridharan, V.; Ruiz. M.,
Menéndez, J. C. Synthesis 2010, 1053.
11. (a) Bouillon, J.-P.; Ates, C.; Janousek, Z.; Viehe, H. G. Tetrahedron Lett. 1993, 34, 5075; (b)
Martins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E. K.; Cunico, W.; Moura, S.; Beck, P.;
Zanatta, N.; Bonacorso, H. G. J. Fluorine Chem. 2003, 123, 261; (c) Saloutin, V. I.; Fomin, A.
N.; Pashkevich, K. I. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1985, 34, 135 (Izv.
Akad. Nauk SSSR, Ser. khim. 1985, 144).
12. Linderman, R. J.; Jamois, E. A. J. Fluorine Chem. 1991, 53, 79.
13. Arens, J. F. Rec. Trav. Chim. Pays-Bas 1955, 74, 271.
14. Staab, H. A.; Walther, G. Chem. Ber. 1962, 95, 2070.
15. Claramunt, R. M.; Sanz, D.; Alkorta, I.; Elguero, J., Foces-Foces, C.; Llamas-Saiz, A. L. J.
Heterocycl. Chem. 2001, 38, 443.

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Graphical abstract
_______________________________________________________________________________
Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-trifluoroacetyl Meldrum’s
acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one and their synthetic usefulness as
(trifluoroacetyl)ketene precursors
Dmitri V. Sevenard,* Andrey V. Didenko, Denis Lorenz, Michael Vorobiev, Johannes Stelten, Thomas Dülcks and
Vyacheslav Ya. Sosnovskikh
________________________________________________________________________